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Parkinsonism Relat Disord. 2018 Oct;55:55-60. doi: 10.1016/j.parkreldis.2018.05.016. Epub 2018 May 18.

Perinatal insults and neurodevelopmental disorders may impact Huntington's disease age of diagnosis.

Author information

1
Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands; Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands; DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, South Africa.
2
Huntington's Disease Centre, Institute of Neurology, University College London, London, UK; Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal; Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal. Electronic address: f.rodrigues@ucl.ac.uk.
3
Department of Neurology, University of the Witwatersrand Donald Gordon Medical Centre, Johannesburg, South Africa.
4
Department of Methodology and Statistics, Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands.
5
Huntington's Disease Centre, Institute of Neurology, University College London, London, UK.
6
Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands; Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands; School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
7
Department of Pediatrics, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands; Department of Translational Neuroscience, School of Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands; Institute of Biomedicine, Facultad de Ciencias Médicas, Universidad Católica de Santiago de Guayaquil, Ecuador.

Abstract

INTRODUCTION:

The age of diagnosis of Huntington's disease (HD) varies among individuals with the same HTT CAG-repeat expansion size. We investigated whether early-life events, like perinatal insults or neurodevelopmental disorders, influence the diagnosis age.

METHODS:

We used data from 13,856 participants from REGISTRY and Enroll-HD, two large international multicenter observational studies. Disease-free survival analyses of mutation carriers with an HTT CAG repeat expansion size above and including 36 were computed through Kaplan-Meier estimates of median time until an HD diagnosis. Comparisons between groups were computed using a Cox proportional hazard survival model adjusted for CAG-repeat expansion length. We also assessed whether the group effect depended on gender and the affected parent.

RESULTS:

Insults in the perinatal period were associated with an earlier median age of diagnosis of 45.00 years (95%CI: 42.07-47.92) compared to 51.00 years (95%CI: 50.68-51.31) in the reference group, with a CAG-adjusted hazard ratio of 1.61 (95%CI: 1.26-2.06). Neurodevelopmental disorders were also associated with an earlier median age of diagnosis than the reference group of 47.00 years (95% CI: 43.38-50.62) with a CAG-adjusted hazard ratio of 1.42 (95%CI: 1.16-1.75). These associations did not change significantly with gender or affected parent.

CONCLUSIONS:

These results, derived from large observational datasets, show that perinatal insults and neurodevelopmental disorders are associated with earlier ages of diagnosis of magnitudes similar to the effects of known genetic modifiers of HD. Given their clear temporal separation, these early events may be causative of earlier HD onset, but further research is needed to prove causation.

KEYWORDS:

Developmental disorders; Epidemiological; Huntington's disease; Modifier; Neonatal

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